Study Casts New Light on Prozac Mechanism

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Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Prozac®) have been used to treat depression for more than three decades but researchers from INSERM and Hoffmann-La Roche have now shed new light on their mechanism of action. SSRIs are believed to act by inhibiting uptake of serotonin into presynaptic cells, thereby increasing the amount available in the synapse to bind to postsynaptic receptors. Typically, an ‘adaptation phase’ of several weeks is needed before the antidepressant effects are fully manifest and the new study helps to explain this latency. The study identified a key role for microRNA-16 (miR-16) in regulating expression of the serotonin transporter (SERT) which is responsible for the recapture of serotonin. Under normal conditions, SERT is present in serotonergic neurons where levels of miR-16 are low, but expression is silenced in noradrenergic cells by higher levels of miR-16; a reduction of miR-16 in noradrenergic cells causes de novo SERT synthesis.

In mice, chronic treatment with fluoxetine was shown to increase levels of miR-16 in serotonergic cells, leading to reduced SERT expression. The cells also released the neurotrophic factor S100β, which decreased miR-16 in noradrenergic cells, resulting in cells with a mixed phenotype that produced both noradrenaline and serotonin and which were sensitive to fluoxetine. Treatment with fluoxetine thus increases serotonin levels both by preventing reuptake by serotonergic neurons and by stimulating production by noradrenergic neurons through reduction of miR-16.

The study is published in the journal Science.


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